Two new classes of drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2is) and hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (HIF-PHis), are likely to have a significant effect on the management of CKD.
SGLT2is were approved by the Food and Drug Administration for the treatment of diabetes in 2013, and have now been shown to slow the progressive loss of kidney function in both diabetic and nondiabetic kidney disease (12–3). SGLT2is demonstrate mortality benefit for patients with CKD, distinguishing them from renin-angiotensin-aldosterone system inhibitors (RAASis), which have otherwise been the mainstay of treatment for patients with diabetic or proteinuric CKD and which provide mortality benefit for a subset of patients with heart failure with reduced ejection fraction (4). Studies of SGLT2is in nondiabetic CKD have been extremely encouraging and we expect that these medications will soon become standard of care for diabetic or nondiabetic, and proteinuric or nonproteinuric, CKD. The potential benefits of SGLT2is have not been specifically explored in autosomal dominant polycystic kidney disease (ADPKD), because both major trials of SGLT2is in nondiabetic CKD (the ongoing EMPA-KIDNEY study [5] and the recently published DAPA-CKD study [1]) excluded patients with ADPKD.
Separately, HIF-PHis are anticipated to have a major effect in the management of anemia of CKD. The current use of erythropoiesis-stimulating agents (ESAs) involves a complex balance between treating anemia and limiting potential adverse effects of cardiovascular events, hypertension, and loss of vascular access (6). HIF-PHis have beneficial effects on iron metabolism, hypertension, and inflammation (7). However, there are concerns that HIF activation could promote cyst growth (8) when used for treatment of patients with ADPKD.
Here, we examine reasons why patients with ADPKD, who comprise approximately 5% of the ESKD population in the United States, warrant unique consideration regarding treatment with SGLT2is or HIF-PHis. We will review the potential risks and benefits of these medications in ADPKD.
SGLT2is
SGLT2is target sodium-glucose cotransporters in the proximal tubule to induce glycosuria and increase sodium delivery to the macula densa, thereby inducing afferent arteriolar constriction. The subsequent reduction in intraglomerular pressure has been proposed to moderate the work of tubular transport and lower cortical oxygen demand (9). SGLT2is have demonstrated efficacy in slowing decline in kidney function and reducing progression to ESKD (12–3). Dapagliflozin demonstrated a number needed to treat of 19 to prevent a primary composite outcome of a sustained decline in eGFR of at least 50%, occurrence of ESKD, or death from a kidney or cardiovascular event (1). Mechanisms of action, although not fully understood, seem nonspecific and could be beneficial to patients with CKD from any intrarenal process. Supporting this notion, benefits of dapagliflozin were similar for patients with or without type 2 diabetes (1).
By causing glycosuria, natriuresis, and glucose-driven osmotic diuresis, SGLT2is stimulate vasopressin and water reabsorption (10). Vasopressin is known to stimulate cyst growth (11). The selective vasopressin (V2 receptor) antagonist tolvaptan is indicated for patients with ADPKD at risk of rapid disease progression. Using SGLT2is in conjunction with tolvaptan may block the vasopressin-mediated water reabsorption needed to avoid volume depletion with SGLT2is, raising concern for risk of hypovolemia, hypernatremia, and AKI. We have seen AKI develop in a single patient prescribed both tolvaptan and an SGLT2i, which resolved after discontinuation of the SGLT2i. The effects of treatment with both an SGLT2i and tolvaptan on urine output should be further studied in a clinical trial, given the distinct benefits of both classes of medications.
Many patients with ADPKD either cannot tolerate tolvaptan or choose not to use it due to aquaretic side effects and risk of liver injury. Tolvaptan is not indicated for patients with ADPKD who are at lower risk of progression, and may not be beneficial to those over the age of 55, leaving many patients with ADPKD off disease-modifying therapy. They might potentially benefit from the use of an SGLT2i; however, given the concern for stimulation of vasopressin, the effects of SGLT2is in ADPKD in patients off tolvaptan would need to be evaluated.
SGLT2is have been studied in animal models of ADPKD with conflicting results. Cyst epithelial cells are dependent on aerobic glycolysis instead of oxidative phosphorylation (Warburg effect), and hyperglycemia promotes cystogenesis and cyst growth (11). One could hypothesize that, by reducing hyperglycemia, SGLT2is could reduce cystogenesis. However, data on the effects of SGLT2is in various ADPKD rodent models have been inconsistent (11). Han:SPRD rats demonstrated a reduction in proliferation of cyst epithelium when treated with the SGLTi phlorizin (12), but not with dapagliflozin (13). PCK rats demonstrated an increase in cyst volume and albuminuria after treatment with dapagliflozin (14). Because neither of these models are based on PKD1 or PKD2 mutations, these discrepancies highlight the challenges in the existing murine models of polycystic kidney disease (15). Further data on SGLT2is and alterations of the metabolic profile in ADPKD are needed.
It is also important to consider the potential benefits of SGLT2is outside of delaying the loss of kidney function (Figure 1). When studied in a patient population mostly already on RAASis, SGLT2is have shown a greater reduction in the rate of eGFR decline in CKD compared with tolvaptan in ADPKD (Table 1). Direct comparison is limited given that patients with ADPKD have a unique pattern of changes in renal function (16,17). All three agents have been shown to delay progression to ESKD. Only SGLT2is have been shown to provide a mortality benefit for patients with CKD (1234–5,1819202122–23), although both RAASis and SGLT2is provide mortality benefit for patients with heart failure (24). Because cardiovascular disease is the major cause of death in ADPKD, this additional mortality benefit of SGLT2is may be an important consideration for patients with ADPKD.
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Figure 1.: Proposed benefits and risks of therapeutic agents in autosomal dominant polycystic kidney disease. Benefits supported by data are shown with solid green lines. Theoretic benefits (not studied in clinical trials) are shown with dashed green lines. Possible adverse effects are shown with dashed red lines. CV, cardiovascular; ESA, erythropoiesis-stimulating agent; HIF-PHi, hypoxia-inducible factor prolyl hydroxylase inhibitor; RAASi, renin-angiotensin-aldosterone system inhibitor; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
Table 1. -
Major trials evaluating efficacy of RAAS inhibitors, SGLT2 inhibitors, and tolvaptan in kidney disease
| Drug Class |
RAAS Inhibitors (CKD) |
SGLT2 Inhibitors (CKD) |
Tolvaptan (ADPKD) |
| Trial |
RENAAL (19) |
IDNT (20) |
AASK (23) |
HALT-PKD (28) |
CREDENCE (2) |
EMPA-REG OUTCOME (3) |
DAPA-CKD (1) |
TEMPO 3:4 (21) |
REPRISE (22) |
| Study population |
T2DM with nephropathy |
T2DM with nephropathy |
Black patients with HTN |
ADPKD with HTN |
T2DM on RAASi |
T2DM (>80% on RAASi) |
With or without T2DM (>95% on RAASi) |
ADPKD with TKV ≥750 ml (>70% on RAASi) |
ADPKD (>80% on RAASi) |
| Cr 1.3–3.0 mg/dl |
Cr 1.0–3.0 mg/dl for women or 1.2–3.0 mg/dl for men |
eGFR 20–65 ml/min per 1.73 m2
|
eGFR >60 ml/min per 1.73 m2
|
eGFR 30–90 ml/min per 1.73 m2
|
eGFR ≥30 ml/min per 1.73 m2
|
eGFR 25–75 ml/min per 1.73 m2
|
eGFR ≥60 ml/min per 1.73 m2
|
eGFR 25–65 ml/min per 1.73 m2 for ages 18–55 |
| UACR ≥300 mg/g |
Urine protein ≥900 mg per 24 hr |
UACR 300–5000 mg/g |
UACR 200–5000 mg/g |
eGFR 25–44 ml/min per 1.73 m2 for ages 56–65 |
| Intervention |
50–100 mg losartan or placebo |
300 mg irbesartan, 10 mg amlodipine, or placebo |
2.5–10 mg ramipril, 5–10 mg amlodipine, or 50–200 mg metoprolol |
Lisinopril with placebo, or lisinopril with telmisartan |
100 mg canagliflozin or placebo |
10 mg or 25 mg empagliflozin or placebo |
10 mg dapagliflozin or placebo |
Tolvaptan (average 95 mg/d) or placebo |
Tolvaptan (90/30 mg or 60/30 mg) or placebo |
| Target BP: standard (120/70–130/80 mm Hg) or low (95/60–110/75 mm Hg) |
| No. of patients |
1513 |
1715 |
1094 |
558 |
4401 |
7020 |
4304 |
1445 |
1370 |
| Follow-up |
3.4 yr |
2.6 yr |
3–6.4 yr |
5–8 yr |
2.6 yr |
3.1 yr |
2.4 yr |
3 yr |
1 yr |
| Main outcomes (intervention compared with placebo) |
Composite of ESKD, doubling of Cr, or death; RR, 16% (95% CI, 2 to 28) |
Composite of ESKD, doubling of Cr, or death; RR, 20% (95% CI, 3 to 34) with irbesartan compared with placebo; RR, 23% (95% CI, 7 to 37) with irbesartan compared with amlodipine |
Composite of ESKD, reduction in eGFR by ≥50%, or death; RR, 22% (95% CI, 1 to 38) with ramipril compared with metoprolol; RR, 38% (95% CI, 6 to 59) with ramipril compared with amlodipine |
Increase in TKV per yr; 6% in low BP group, 7% in standard BP group |
Composite of ESKD, doubling of Cr, or kidney-/CV-related death; HR, 0.70 (95% CI, 0.59 to 0.82) |
Composite of ESKD, doubling of Cr, or kidney related death; HR, 0.54 (95% CI, 0.40 to 0.75) |
Composite of ESKD, sustained decline in eGFR of at least 50%, or kidney-/CV-related death; HR, 0.56 (95% CI, 0.45 to 0.68) |
Composite of time to worsening Cr, pain, HTN, or albuminuria; 44 events per 100 patient-years with tolvaptan, and 50 events per 100 patient-years with placebo |
Change in eGFR per yr; −2.34 with tolvaptan and −3.61 with placebo (difference, 1.27) |
| Change in eGFR per year, −4.4 with losartan and −5.2 with placebo (difference, 0.8) |
Change in CrCl per year, -5.5 with irbesartan, −6.8 with amlodipine, and −6.5 with placebo (differences, 1.3 and 1.0, respectively) |
Change in eGFR per year, −1.81 with ramipril and −2.42 with metoprolol (difference, 0.61) |
Change in eGFR per year, −2.9 in low BP group, −3.0 in standard BP group |
Change in eGFR per year, −3.19 with canagliflozin and −4.71 with placebo (difference, 1.52) |
Change in eGFR per year, −0.19 with empagliflozin and −1.67 with placebo (difference, 1.48) |
Change in eGFR per year, −1.67 with dapagliflozin and −3.59 with placebo (difference, 1.92) |
Increase in TKV per yr, 3% with tolvaptan and 6% with placebo |
| Similar findings in lisinopril/ placebo group compared with lisinopril/ telmisartan group |
Change in eGFR per year, −2.72 with tolvaptan and −3.70 with placebo (difference, 0.98) |
| Common side effects |
Hyperkalemia, cough (ACE-I) |
Genital mycotic infections, hypovolemia |
Aquaresis, LFT abnormalities |
| Cost |
$ |
$$ |
$$$$ |
Common side effects and cost are listed for each class and are not specific to individual trials. Patients with
ADPKD were not specifically studied in trials of RAASi and
SGLT2i, with the exception of HALT-PKD (
16,
17). RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium-glucose cotransporter-2;
ADPKD, autosomal dominant polycystic kidney disease; T2DM, type 2 diabetes mellitus; HTN, hypertension; RAASi, RAAS inhibitors; TKV, total kidney volume; Cr, creatinine; UACR, urine albumin-creatinine ratio; RR, relative risk; CV, cardiovascular; CrCl, creatinine clearance; ACE-I, angiotensin-converting enzyme inhibitor; LFT, liver function test;
SGLT2i, SGLT2 inhibitors. 95% CI, 95% confidence interval.
Recently, the mineralocorticoid antagonist (MRA) finerenone also showed a benefit in cardiovascular disease in patients with CKD and type 2 diabetes (25). MRAs have been shown to decrease BP in early ADPKD (26), and show beneficial effects in a rodent model (27). However, MRAs were not permitted in the HALT-PKD study (28) and have not been otherwise extensively studied in ADPKD.
SGLT2is have been reported to promote erythrocytosis by indirectly increasing expression of HIF-2α (29). As explained below, this effect may speak in favor of the unique benefits of this class of agents and may offer a novel pathway for treatment of anemia for patients with ADPKD.
HIF-PHis
A key regulatory function of the kidneys is oxygen-regulated expression of erythropoietin. This process occurs through HIF-α, which is marked for degradation by prolyl hydroxylases in states of normoxia, but binds to HIF-β to activate nuclear transcription of hypoxia response elements, including EPO, in states of hypoxia (67–8). HIF-2α is found in glomerular and peritubular cells and is the primary HIF-α isoform responsible for erythropoietin production, whereas HIF-1α is found in tubular epithelial cells.
In polycystic kidneys, cysts can compress nephrons and vasculature, resulting in local hypoxia and induction of HIF-α (8). An increase in HIF-2α likely explains the commonly observed phenomenon of patients with ADPKD having lesser degrees of anemia, with less need for ESAs. However, induction of HIF-1α increases chloride-dependent fluid secretion and promotes a switch from oxidative phosphorylation to glycolysis, thereby promoting cyst expansion. HIF-1α levels are high in human and rat ADPKD kidneys, and HIF-1α and HIF-2α expression levels correlate with cyst burden. Other mechanisms by which HIF-1α could regulate cyst growth are unclear, because HIF-1α has been shown in different systems to be both pro- and antiapoptotic, and pro- and antiproliferative (8).
These data raise concern for increasing cyst growth when treating patients with pre-ESKD ADPKD with HIF-PHis (Figure 1). However, given the significant burden that anemia can pose to the quality of life of patients, a risk-benefit analysis in the context of other available treatment options must be considered. Patients with anemia of CKD have relative deficiencies in erythropoietin production and are often unable to properly use iron stores. They are treated with ESAs and iron, which can worsen functional iron deficiency and inflammation (6). HIF-PHis have been shown to increase hemoglobin values in dialysis- and non–dialysis-dependent CKD, while also decreasing hepcidin levels and reducing intravenous iron requirements (7). A post hoc analysis of patients with pre-ESKD ADPKD who were enrolled in clinical trials of HIF-PHi efficacy may help address the concern for potential acceleration of cyst growth and loss of kidney function; however, the small numbers of patients with cystic kidney disease (136 of 2761 patients in the Olympus trial of the HIF-PHi roxadustat [30]) in these trials may limit analysis.
Current HIF-PHis stabilize both HIF-1α and -2α isoforms, although there are no data regarding changes in HIF-1α and HIF-2α expression levels. If there is an agent that predominantly stabilizes HIF-2α, it may be possible for HIF-PHis to provide a greater benefit than risk for patients with ADPKD. SGLT2is are proposed to suppress HIF-1α while activating HIF-2α (29), potentially providing a unique mechanism to safely activate HIF-driven erythropoiesis for patients with cystic kidney disease.
Until further data are available to understand the potential effect of HIF-PHis on cyst development and growth, we suggest limiting their use in patients with pre-ESKD ADPKD.
Conclusions
Patients with ADPKD represent a significant portion of the CKD and ESKD population. Whether they are at low or high risk of disease progression, the nephrology community should be able to offer disease-modifying agents that are effective and safe. Tolvaptan reduces progression of kidney disease and delays onset of kidney failure (18,21,22); however, it carries a significant burden of side effects and monitoring to minimize risk of toxicity. We would favor a randomized controlled trial of SGLT2is for patients with ADPKD who are not candidates for tolvaptan. We discourage use of HIF-PHis in patients with non–dialysis-dependent ADPKD, unless they have failed treatment with traditional therapies. All treatment should be aimed at keeping target hemoglobin within the national guidelines. In this era of an expanding armamentarium in treating CKD, we eagerly await definitive clinical trials studying the use of these novel therapies in patients with ADPKD.
Disclosures
N.K. Dahl reports being the principal investigator for clinical trials sponsored by Allena, Bayer, Kadmon, Regulus, Reata, and Sanofi; serving on the medical advisory board for National Kidney Foundation New England Chapter and ESKD Network, Region 1; receiving honoraria from the National Kidney Foundation and Otsuka Pharmaceutical; having consultancy agreements with Otsuka Pharmaceuticals; serving as a scientific advisor for, or member of, the PKD Foundation and Natera. The remaining author has nothing to disclose.
Funding
None.
Acknowledgments
The authors acknowledge valuable input from Dr. Whitney Besse and Dr. Stefan Somlo in reviewing this manuscript.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or Kidney360. Responsibility for the information and views expressed herein lies entirely with the author(s).
Author Contributions
N.K. Dahl provided supervision; and N.K. Dahl and D.M. Patel conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.
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